Will a Nonautologous Cancer Vaccine Be the Next to Make It Through Approval?

In the race to mimic Dendreon’s success with Provenge, off-the-shelf products make for attractive opportunities.

In the race to mimic Dendreon’s success with Provenge, off-the-shelf products make for attractive opportunities.[Alexandre Boavida - Fotolia.com]

Dendreon’s Provenge may have the distinction of being the first therapeutic cancer vaccine on the market, but it may not be the only one for too much longer. While Provenge is an autologous treatment and a number of other such vaccines are in development, nonautologous cancer vaccines are also vying for attention. In some ways pharma companies and investors may even prefer these off-the-shelf (OTS) therapies to avoid the expensive and complex manufacturing that goes along with patient-specific vaccines.

A Datamonitor report due in December, entitled "Pipeline Insight: Therapeutic Cancer Vaccines—Prospect of first approval set to reinvigorate interest from major companies," says high risk and uncertain rewards have limited larger companies’ involvement in therapeutic cancer vaccines.

Nonetheless GlaxoSmithKline (GSK) and Merck KGaA have made significant commitments to nonautologous vaccines. Of the 12 cancer vaccines in late-phase development, Stimuvax (Merck KGaA/Oncothyreon) and MAGE-A3 ASCI (GlaxoSmithKline) have the highest clinical and commercial potential, the report projects.

Stimuvax is a BLP25 liposomal therapeutic vaccine designed to induce an immune response to cancer cells expressing MUC1, an antigen seen on many cancers including lung, breast, prostate, and colorectal cancers. The vaccine incorporates a 25-amino acid MUC-1 sequence in a liposomal formulation and is thought to work by stimulating a T-cell mediated anti-MUC-1 response to cancer cells expressing the protein target.

GSK’s MAGE-A3 consists of the tumor-specific antigen epitope 3, which is expressed in about 40% of all non-small-cell lung cancer (NSCLC) tumors, according to the company. Epitope 3 is also present in a large enough proportion of patients to make it an off-the-shelf vaccine.

Most Advanced Candidates

Stimuvax is being developed by Merck through a licensing agreement with Oncothyreon, which reported a $14.9 million private placement in September. About three months earlier Merck was cleared to restart two of three Phase III trials testing the vaccine. The FDA had halted two lung cancer trials and a breast cancer trial, which together involved a total of 26,000 patients.

While the lung cancer trials have resumed, the breast cancer study remains on hold. Ongoing Phase III studies include patients who will have a lower tumor burden than those involved in the Phase IIb trial.

GSK began clinical investigation of MAGE-A3 in 2007 with a study involving 400 centers in 33 countries. Though it was tested in NSCLC patients, it is also being developed to treat malignant melanoma.

GSK’s kitchen-sink approach to making its vaccine uses the entire 360 amino acid-long MAGE-A3 protein as an antigen to maximize the number of epitopes packed in liposomes and delivered with proprietary adjuvant mixes that may include: the immunostimulatory portion of GSK’s adjuvant MPA; QS-21, a lipid mix from Antigenics and CpG oligonucleotide; and a toll-like receptor 9 agonist originally developed at Coley Pharmaceutical, which was purchased by Pfizer in 2007.

Kitchen sink or not, encouraging results from the Phase II NSCLC study have led to a Phase III trial evaluating MAGE-A3 as an adjuvant therapy in about 2,270 MAGE-A3-positive patients with completely resected stage IB, II, or IIIA NSCLC.

Also In the Pipeline

Relatively small companies are also seeing investor interest in OTS therapeutic cancer vaccines. Immatics Biotechnologies recently raised €53.8 million (about $68.5 million) in a Series C financing to advance its therapeutic cancer vaccine pipeline. Lead product IMA901 consists of peptides derived from a medley of synthetically produced tumor-associated peptides (TUMAPS) frequently over-expressed in most patients suffering from renal cell carcinoma.

Later this year the firm hopes to start a Phase III renal cancer trial with primary endpoint as overall survival. Initial results are expected toward the end of 2013.

Additionally, enthusiasm for cancer therapeutic vaccines spiked after Celldex reported positive Phase IIb results with rindopepimut (CDX-110), a glioblastoma multiforme (GBM) vaccine that was partnered with Pfizer until this September. In 2008, Pfizer paid $40 million up front plus $10 million in equity investments and assumed responsibility for the Phase IIb trial. Celldex stood to receive about $390 million in milestones plus double-digit royalties if the product reached commercialization.

Pfizer said that it returned rights to Celldex because the cancer vaccine no longer fit with its strategic plans despite the impressive interim data presented at the 2010 American Society of Clinical Oncology meeting. With regard to Pfizer returning rights to rindopepimut, Celldex’ svp and CMO, Thomas Davis, M.D., told GEN, “Our current resources are sufficient to complete our ongoing clinical study. There is a lot of interest in rindopepimut, there are multiple routes to achieving our goal, and we don’t see it as a major hurdle.”

Rindopepimut was studied in three open-label clinical studies that evaluated the vaccine in combination with temozolomide. The company reported that the treatment produced a 70% progression-free survival rate, corresponding to the 8.5-month rate seen in the company’s other two GBM trials.

Based on historic controls from Duke University and The University of Texas MD Anderson Cancer Center, median progression-free survival for patients with EGFRvIII-positive GBM was 6.3 months. Celldex anticipates reporting further results at a meeting being held by the Society of Neuro-Oncology next month.

Rindopepimut comprises a peptide based on amino acid regions flanking the extracellular portion of EGFRvIII. “In EGFRvIII the most common mutation of the normal receptor protein, the extracellular portion of the peptide, is spliced out, and you are left with a new sequence of amino acids on the cell surface,” Dr. Davis explained to GEN.

“The external sequence resulting from the splice makes a perfect cancer target because it is not found in normal tissues, and it is highly immunogenic.” The peptide vaccine is administered to patients along with granulocyte-macrophage colony-stimulating factor and keyhole limpet hemocyanin as a carrier protein and adjuvant.

Celldex believes that its next-generation vaccines will be based on its antigen-presenting cell (APC) targeting technology consisting of antibodies that are specific for APC receptors known to be “entry portals” for antigen-processing pathways. APCs can internalize these targeted antigens into cellular compartments, process them, and then present them on the cell surface to initiate the desired immune response that could, potentially, avoid isolation of autologous patient cells.

“Beyond rindopepimut we may combine EGFRvIII with other brain-tumor targets,” Dr. Davis told GEN. “Long term we would like to attack tumors by using more antigens that appear on brain tumor cell surfaces.”

An article published in the January 2009 issue of Expert Reviews stated that scientists and clinical cancer vaccine developers “cannot be anything other than troubled by the sheer number of Phase III clinical trial failures.” But the review also noted that these failures have yielded significant knowledge and improved understanding of how the immune system interacts with cancer.

OTS cancer vaccines indeed have their own manufacturing complications and have yet to establish their efficacy in the clinic. Yet they offer the most compelling choice for pharma companies and investor interest.